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Management of acute seizure and status epilepticus
Apisit Boongird, MD
Division of Neurology
Ramathibodi Hospital
Sunday August 27 10.00-10.45
Bangsan
Objectives
• Acute repetitive seizure
• Status epilepticus
Definition of epileptic seizure by the
International League Against Epilepsy (ILAE)
• An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Epilepsia, 46(4):470–472, 2005
Acute repetitive seizures (Seizure clusters)
Acute repetitive seizures (ARS)
• Home
• OPD
• IPD
Acute Repetitive Seizures (ARS)
• The practical definition of acute repetitive seizures has not been established.
• Acute repetitive seizures is neurologic emergency and a common clinical phenomenon describing an increase in seizures occurring over a specific period of time (ranging from several minutes up to 24 hours).
• Acute repetitive seizures may include any type of seizure and may vary in severity, but by definition there is complete recovery in between seizures.
Curr Opin Neurol 2015;28(2):143Y150.
Management of acute repetitive seizures (ARS)
• Stop the seizures
• Identify the etiology of acute repetitive seizures
• Benzodiazepines remain the mainstay of therapy.
• The treatment of ARS includes the usage of extra doses of usual antiepileptic medications and oral benzodiazepines (diazepam or lorazepam) for mild ARS.
• A 45 yo presented with first unprovoked seizures.
seizure type 1: left face clonic with preserved awareness
seizure duration: 5 minutes
Treatment: LEV 500-500 + sx
• In August 2560, he had ARS for 2 hours.
Outpatient acute benzodiazepine therapy
• Rectal diazepam is the only currently marketed treatment available for use by nonmedical caregivers in the USA, and buccal midazolam is approved in the European Union.
Outpatient acute benzodiazepine therapy
Medications Formulation Notes
Diazepam oral tablet
rectal gel (FDA approved) N Engl J Med 1998;
338:1869–1875. and Neurology 1998; 51:1274–1282.
intramuscular
Midazolam buccal
intranasal
intramuscular N Engl J Med 2012;
366:591–600 (The Rapid Anticonvulsant Medication Prior to Arrival
Trial (RAMPART) in pre-hospital status epilepticus
Lorazepam oral tablet
intranasal
sublingual
Progesterone cyclic natural progesterone catamenial epilepsy Neurology 2014; 83:345–348.
CNS Drugs (2015) 29:55–70
Oromucosal midazolam (solution Buccolam)
https://www.medicines.org.uk
Age range Dose Label colour
3 to 6 months hospital setting 2.5 mg Yellow
> 6 months to < 1 year 2.5 mg Yellow
1 year to < 5 years 5 mg Blue
5 years to < 10 years 7.5 mg Purple
10 years to < 18 years 10 mg Orange
Standard doses are indicated below:
Carers should only administer a single dose of midazolam. If the seizure has not stopped within 10 minutes after
Status epilepticus (SE)
Old definition of SE
• A definition of more than 30 minutes of continuous seizure activity or two or more sequential seizures without full recovery of consciousness between was widely adopted, citing neuronal damage in animal models beyond this timeframe.
Epilepsy Foundation, 1993
Cerebral changes Systemic and metabolic
changes
Autonomic and
cardiovascular changes
increased cerebral blood flow hyperglycemia increased blood pressure
increased cerebral
metabolism
lactic acidosis increased cardiac output
increased lactate
concentration
massive catecholamine
release
increased glucose
concentration
cardiac dysthymia
urine incontinence
Phase 1: compensation
J Neurol Neurosurg Psychiatry 2001;70(suppl II):ii22–ii27
Phase 2: decompensation
Cerebral changes Systemic and metabolic
changes
Autonomic and
cardiovascular changes
failure of cerebral
autoregulation
hypoglycemia hypoxia
hypoxia hypokalemia/ hyperkalemia falling blood pressure
hypoglycemia metabolic and respiratory
acidosis
falling cardiac output
increased intracranial
pressure and cerebral oedema
hepatic and renal dysfunction cardiac failure
consumptive coagulopathy respiratory failure
DIC hyperpyrexia
rhabdomyolysis,
myoglobinuria
J Neurol Neurosurg Psychiatry 2001;70(suppl II):ii22–ii27
“Status epilepticus is a condition resulting either from the failure of the mechanisms
responsible for seizure termination or from the initiation of mechanisms, which lead to
abnormally, prolonged seizures (after time point t1). It is a condition, which can have
long-term consequences (after time point t2), including neuronal death, neuronal injury,
and alteration of neuronal networks, depending on the type and duration of seizures”.
Epilepsia, 56(10):1515–1523, 2015
• Status epilepticus represents the persistence of abnormal excitation and the ineffective recruitment of inhibition.
J Clin Neurophysiol1995;12(4):326Y342.
Type of SE Operational dimension 1
Time (t1), when a seizure is
likely to
be prolonged leading to
continuous
seizure activity
Operational dimension 2
Time (t2), when a seizure may
cause long term consequences
(including neuronal injury,
neuronal death, alteration
of neuronal networks and
functional deficits)
Tonic- clonic SE 5 min 30 min
Focal SE with
impaired
consciousness
10 min > 60 min
Absence status
epilepticus
10-15 mina unknown
Epilepsia, 56(10):1515–1523, 2015a= Evidence for the time frame is currently limited and future data may lead to modifications
Classification of SE by the ILAE
• 1 Semiology
• 2 Etiology
• 3 EEG correlates
• 4 Age
Epilepsia, 56(10):1515–1523, 2015
Axis 1: Semiology
• The presence or absence of prominent motor symptoms
• The degree (qualitative or quantitative) of impaired consciousness
Epilepsia, 56(10):1515–1523, 2015
Axis 1: Classification of status epilepticus (SE)
A) With prominent motor symptoms
A.1 Convulsive SE (CSE, synonym: tonic–clonic SE)
A.1.a. Generalized convulsive
A.1.b. Focal onset evolving into bilateral convulsive SE
A.1.c. Unknown whether focal or generalized
A.2 Myoclonic SE (prominent epileptic myoclonic jerks)
A.2.a. With coma
A.2.b. Without coma
A.3 Focal motor
A.3.a. Repeated focal motor seizures (Jacksonian)
A.3.b. Epilepsia partialis continua (EPC)
A.3.c. Adversive status
A.3.d. Oculoclonic status
A.3.e. Ictal paresis (i.e., focal inhibitory SE)
A.4 Tonic status
A.5 Hyperkinetic SE
Epilepsia, 56(10):1515–1523, 2015
(B) Without prominent motor symptoms (i.e., non- convulsive SE, NCSE)
B.1 NCSE with coma (including so-called “subtle” SE)
B.2 NCSE without coma
B.2.a. Generalized
B.2.a.a Typical absence status
B.2.a.b Atypical absence status
B.2.a.c Myoclonic absence status
B.2.b. Focal
B.2.b.a Without impairment of consciousness (aura continua, with autonomic, sensory,
visual, olfactory, gustatory, emotional/ psychic/experiential, or auditory symptoms)
B.2.b.b Aphasic status
B.2.b.c With impaired consciousness
B.2.c Unknown whether focal or generalized
B.2.c.a Autonomic SE
Axis 1: Classification of status epilepticus (SE)
Epilepsia, 56(10):1515–1523, 2015
Axis 2: Etiology
• Known (i.e., symptomatic)
- Acute (e.g., stroke, intoxication, malaria, encephalitis, etc.)
- Remote (e.g., posttraumatic, postencephalitic, poststroke, etc.)
- Progressive (e.g., brain tumor, Lafora’s disease and other PMEs, dementias)
- SE in defined electroclinical syndromes
• Unknown (i.e., cryptogenic)
Epilepsia, 56(10):1515–1523, 2015
Axis 3: Electroencephalographic correlates
• Currently there are no evidence-based EEG criteria for SE.
Epilepsia, 56(10):1515–1523, 2015
EEG patterns in SE
1. Location: generalized (including bilateral synchronous patterns), lateralized, bilateral independent,
multifocal.
2. Name of the pattern: Periodic discharges, rhythmic delta activity or spike-and-wave/sharp- and-wave
plus subtypes.
3. Morphology: sharpness, number of phases (e.g., triphasic morphology), absolute and relative amplitude,
polarity.
4. Time-related features: prevalence, frequency, duration, daily pattern duration and index,
onset (sudden vs. gradual), and dynamics (evolving, fluctuating, or static).
5. Modulation: stimulus-induced vs. spontaneous.
6 Effect of intervention (medication) on EEG.
Epilepsia, 56(10):1515–1523, 2015
Axis 4: Age
1. Neonatal (0 to 30 days)
2. Infancy (1 month to 2 years)
3. Childhood (> 2 to 12 years)
4. Adolescence and adulthood (> 12 to 59 years)
5. Elderly (≥ 60 years)
Epilepsia, 56(10):1515–1523, 2015
Generalized convulsive status epilepticus (GCSE)
Definition of CSE
• CSE is a convulsive seizure lasting more than 5 min or consecutive seizures without recovery of consciousness.
• In the case of convulsive SE, both time points (t1 at 5 min and t2 at 30 min) are based on animal experiments and clinical research.
Epilepsia, 56(10):1515–1523, 2015
Key points
• Principle of treatment
1. Stop both ongoing clinical and electrographic seizures
2. Identify and treat the etiology of CSE
3. diagnosis and treatment of complications of CSE
Time is the brain
• The response to treatment with anti-seizure medications is decreasing with time and ongoing seizures probably due to the following reasons;
- internalization of GABA receptors
- the upregulation of drug-efflux transporters such as P- glycoprotein
- an increment of pro-inflammatory agents
Ann N Y Acad Sci 2016;1378:166–73.
Epilepsia 2009;50(Suppl. 8):19–21.
Choosing the anti-seizure medications
• Age
• Clinical seizure type
• Comorbidities
- cardiovascular disease
- liver disease
- kidney disease
• History of drug allergy
- minor rash to SJSs
• Anti-seizure medications
- administration
- mechanism of action
- pharmacodynamics
- pharmacokinetics
- efficacy for each seizure type
- recommended doses
- adverse effects
- drug interactions
Treatment phases of CSE
• Stage 1 (early or impending CSE)
- Benzodiazepines are the drugs of choice.
- RAMPART (Rapid Anticonvulsant Medication Prior to Arrival Trial)
IV lorazepam vs IM midazolam*
- AES guideline state that IM midazolam has a superior effectiveness
compared to intravenous lorazepam in adults with CSE without
established intravenous access (Level A)***N Engl J Med 2012; 366:591-600
**Epilepsy Curr 2016;16:48–61.
Treatment phases of CSE
• Stage 2 (Established SE) : CSE persisting after first-line treatments
- phenytoin (fosphenytoin)
- phenobarbital
- valproic acid
- levetiracetam
- lacosamide
Treatment phases of CSE
• Stage 3 (refractory CSE): CSE persisting > 60 minutes after second-line treatments
- Hemodynamic monitoring
- EEG monitoring
- Initiation of anesthetic agents
- Midazolam
- Propofol
- Thiopental
- Ketamine
- Goals
- stop ongoing seizure
- EEG background suppression VS burst suppression
Therapeutic monitoring
• Objectives
- to monitor the therapeutic response
- to avoid side effects of therapy
• Hemodynamic and respiratory monitoring
- pulse oximetry
- monitor Bp, HR, O2 sat
- EKG monitoring
• Clinical neurophysiologic test
- Continuous EEG monitoring
Treatment phases of CSE
• Stage 3 (refractory CSE): CSE persisting after second-line treatments
- Anesthetic agents are the drugs of choice for the treatment of refractory CSE. It is required to secure the airway and start mechanical ventilation if the patient is not already intubated for other reasons.
- If no seizure for 24- 48 hours, then tapering off anesthetic agents
- Adequate anti-seizure medications should be prescribed to the patient while the anesthetic agent is being withdrawn.
- avoid anti-seizure medications with a primarily GABAergic mechanism
- avoid > 2 anti-seizure medications
- try anti-seizure medications with multiple mechanisms of action and low drug interactions
NeurocritCare 2012;17:3–23.
Treatment phases of CSE
• Stage 4 (super-refractory CSE)*: CSE persisting for more than 24 hours after administration of third-line treatments
- anesthetic agents
- ketamine
- immunomodulatory therapy
- hypothermia
- new anti-seizure medications
- ketogenic diet*
*Brain 2011;134:2802–18.
**Neurology. 2017 Mar 7;88(10):938-943.
The US Department of Veterans Affairs (VA) Cooperative Study randomized controlled clinical trial
N Engl J Med 1998;339(12):792Y798
Conclusions
As initial intravenous treatment for overt generalized convulsive status epilepticus, lorazepam is more effective
than phenytoin. Although lorazepam is no more efficacious than phenobarbital or diazepam and phenytoin, it is
easier to use.
518 pts with GCSE
Five-year randomized, double blind, multicenter trial of four intravenous regimens
1.Lorazepam 2.Phenobarbital 3.Phenytoin 4. Diazepam
followed by Phenytoin
Classified into
1. Overt SE (n=384 pts)
2. Subtle SE (n= 134 pts)
http://thaiepilepsysociety.com
http://thaiepilepsysociety.com
http://thaiepilepsysociety.com
http://thaiepilepsysociety.com
http://thaiepilepsysociety.com
http://thaiepilepsysociety.com
Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society
Epilepsy Currents, Vol. 16, No. 1 (January/February) 2016 pp. 48–61
Epilepsy Currents, Vol. 16, No. 1 (January/February) 2016 pp. 48–61
Phenytoin in GCSE
• Efficacy
• Administration
• Adverse effects
• Allergy
• Enzyme inducing properties
NeurocritCare 2013;18:193–200.
The Established Status Epilepticus Treatment Trial (ESETT)
• This ESETT is currently enrolling patients and is designed to determine the most effective and/or the least effective treatment of ESE among patients older than 2 years by comparing three arms: fosphenytoin (fPHT), levetiracetam (LVT), and valproic acid (VPA).
Epilepsia 2013;54:89–92.
Non-convulsive status epilepticus (NCSE)
Non-convulsive status epilepticus (NCSE)
• Patients with NCSE may have no clinical signs or develop only subtle jerks of the face, eyes, and extremities.
• NCSE is diagnosed only by electroencephalography(EEG).
(B) Without prominent motor symptoms (i.e., non- convulsive SE, NCSE)
B.1 NCSE with coma (including so-called “subtle” SE)
B.2 NCSE without coma
B.2.a. Generalized
B.2.a.a Typical absence status
B.2.a.b Atypical absence status
B.2.a.c Myoclonic absence status
B.2.b. Focal
B.2.b.a Without impairment of consciousness (aura continua, with autonomic, sensory,
visual, olfactory, gustatory, emotional/ psychic/experiential, or auditory symptoms)
B.2.b.b Aphasic status
B.2.b.c With impaired consciousness
B.2.c Unknown whether focal or generalized
B.2.c.a Autonomic SE
Axis 1: Classification of status epilepticus (SE)
Epilepsia, 56(10):1515–1523, 2015
Salzburg EEG consensus criteria for nonconvulsive status epilepticus (SCNC)
Lancet Neurol 2016;15(September (10)) 1054–62Epilepsy Behav: E&B 2015;49(August)158–63
Patients without known epileptic encephalopathy
• EDs > 2.5 Hz, or
• EDs ≤ 2.5 Hz or rhythmic delta/theta activity (> 0.5Hz) AND one of the following:
- EEG and clinical improvement after IV AED*, or
- Subtle clinical ictal phenomena, or
- Typical spatiotemporal evolution**
Patients with known epileptic encephalopathy
• Increase in prominence or frequency when compared to baseline with observable change in clinical state
• Improvement of clinical and EEG* features with IV AEDs
* If EEG improvement without clinical improvement, or if fluctuation without definite evolution, this should be
considered possible NCSE.
** Increment onset(increase in voltage and change in frequency), or evolution in pattern(change in frequency >
1Hz or change in location), or decrementing termination(voltage and frequency).
EDs: epileptiform discharges(spikes, polyspikes, sharp-waves, sharp-and-wave complexes)
IV AED: intravenous antiepileptic drugs
• A 17-yo male with past medical history of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome presents to the emergency department with status epilepticus for 30 minutes.
MELAS
midazolam + levetiracetam
American Clinical Neurophysiology Society’s Standardized Critical Care EEG Terminology: 2012 version
J Clin Neurophysiol 2013;30: 1–27
Epilepsy & Behavior 49 (2015) 158–163
Epilepsy & Behavior 49 (2015) 158–163
Epilepsia partialis continua (EPC)
Epilepsia partialis continua (EPC)
• Prevalence 1: 1,000,000
• 5-10 patients per year at Faculty of Medicine, Prince of SongklaUniversity
• Segmental myoclonic seizures
• The most frequent distribution of EPC involved the face and arms (42.7%)
Paiboonpol S.J Med Assoc Thai. 2005 Jun;88(6):759-62
Epilepsy Res. 2012 Jun;100(1-2):179-87.
Epilepsia partialis continua (EPC)
• Treatment
- identify and treat causal or precipitating factors
- anti-seizure medications
- first-generation: carbamazepine, valproate,
clonazepam
- second-generation: topiramate, levetiracetam
Conclusions
• Status epilepticus (SE) requires not only urgent symptomatic treatment with antiepileptic drugs but also rapid identification and treatment of its cause.
The end